The overall objective of this research is the synthesis of adriamycin and daunorubicin analogs and derivatives with a view to improving the therapeutic efficacy, extending the antitumor spectrum, or reducing the toxicity of the parent substances. The naphthacenequinone glycosides daunorubicin and adriamycin are clinically important antitumor antibiotics derived from Streptomyces fermentations. Daunorubicin is effective in inducing remission in acute leukemia; adriamycin (14-hydroxydaunorubicin) in addition shows great promise against a variety of solid tumors in children and adults. This greater antitumor effectiveness of adriamycin vs. daunorubicin provides the hope that chemical synthesis of adriamycin analogs and derivatives may result in products with even greater therapeutic potential. This proposal is directed toward the preparation of adriamycin analogs and derivatives modified specifically in either or both the C-9 acetyl side-chain or the glycosidic moiety. From biochemical, biophysical, and pharmacological consideratons, structural changes at these sites are expected to give products with continued high antitumor activity but with pharmacology differing from that of the parent substance. This proposal further provides for preliminary bioassay of target compounds in vitro and in vivo, which studies will evaluate the effectiveness of synthetic agents and provide a guide for further chemical modifications. The validity of our rationale and our chemical and biological approach appears to be substantiated by the recent synthesis in our laboratory of a number of products, including some adriamycin ester N-trifluoroacetamides. The latter products were prepared by a synthetic scheme of general applicability to some of the work proposed herein; several of these adriamycin ester amides have produced significantly greater prolongation of survival of mice inoculated with P388 leukemia than that affored by adriamycin itself on the same schedule.